The renin-angiotenin system is one of the most important regulators of blood pressure and salt balance. Inappropriate activity of this system contributes substantially to the pathogenesis of a number of medical problems, including essential hypertension, renovascular hypertension and heart failure. Renin catalyzes the formation from angiotensinogen of angiotensin-I that is converted to angiotensin II with potent vasocontrictor, aldosterone-stimulating and other actions. The control of this enzyme is rate-limiting in this cascade of actions. Thus knowledge of the mechanisms controlling renin gene expression and of potential abnormalities in such control is critical for understanding the pathological states in which renin participates and for devising better means to control them. In the proposed studies it is hoped to utilize the recently cloned human renin chromosomal gene and cDNA sequences and of a hybrid gene that directs the synthesis of prorenin to: study the regulation by Beta-adrenegic agonists, steroid hormones, salt, adenosine and prostaglandins of rabbit renin mRNA in isolated arteriole preparations in which direct vs. indirect actions can be distinguished; determine which extrarenal human tissues express the renin gene; utilize gene transfer approaches to determine the DNA elements responsible for tissue-specific and constitutive expression of the human renin gene and to understand the mechanisms by which regulatory mediators affect its expression; and to determine the ability of various cell types to process prorenin to renin. Finally, taking advantage of recent findings of polymorphisms in the human renin gene it is planned to examine the DNAs from patients to determine whether these or other polymorphisms correlate with clinical states, including essential and other forms of hypertension in which renin gene expression is abnormal. These studies should provide information relevant to the understanding, diagnosis and treatment of hypertensive and related disorders, including that about: (i) basic mechanisms by which renin gene expression and the conversion of prorenin to renin are controlled; (ii)\extrarenal renin-angiotensin systems; (iii) structures on DNA important for renin gene expression and its regulation; and, (iv) whether abnormalities in the gene are responsible for impaired responsiveness of the renin-angiotensin system in disease.